Organ and tissue adhesions frequently occurring after surgery are just one of the natural phenomena that occur during cell proliferation and regeneration in damaged tissues. However, organ and tissue adhesions cause continuous discomfort or dysfunction in patients and require reoperation for adhesiolysis, and even become life-threatening.
Such adhesions occur almost anywhere in the body such as muscle, the sclera, the conjunctiva, a Tenon's capsule, an intermuscular membrane, etc., but it is known that the most clinically severe problems are caused by repeated operations due to peritoneal adhesion or intestinal obstruction following abdominal surgery, excessive bleeding, tissue reaction to suture materials, foreign materials during operation, postoperative inflammation, etc. Therefore, in order to solve postoperative tissue adhesion problems, introducing a physical barrier between an injured tissue and a tissue is a method by which adhesion can be prevented.
To solve postoperative tissue adhesion problems, there have been many attempts to inhibit adhesion between tissues after surgery by using various adhesion inhibitors. Preclude, (W. L. Gore) prepared by using a non-degradable polymer Teflon, Interceed (Johnson & Johnson Medical), prepared by oxidation of a degradable polymer cellulose, Seprafilm (Genzyme), prepared by crosslinking of hyaluronic acid and carboxymethyl cellulose, and Oxiplex (FzioMed), prepared by crosslinking of high-molecular-weight polyethylene oxide and carboxymethyl cellulose, have been used as film-type materials. A non-degradable polymer substantially separates wounds, showing excellent anti-adhesion performance, but exists as a foreign body in the body after an operation, thereby causing inflammation in surrounding tissues or acting as an obstacle to tissue regeneration. Therefore, in some cases, reoperation is required to remove the non-degradable polymer after a certain period of time. A biodegradable polymer is advantageous in that it is degraded and eliminated from the body after a certain period of time, and therefore, does not exist as a foreign body. However, anti-adhesion performance of a degradable polymer is still rather lower than that of a non-degradable polymer. Further, the use of film-type anti-adhesion barriers requires stitching with surrounding tissues using a suture thread in order to prevent movement of the anti-adhesion barrier at the site of application, and the biggest problem is that tissue adhesion frequently occurs at the suture site and it is difficult to introduce film-type anti-adhesion barriers when the site of application is complex, microscopic or tubular-shaped.
To overcome these problems, gel-type carboxymethylcellulose, dextran 70, Flowgel (Mediventures), prepared by using a polyethylene oxide-polypropylene oxide copolymer (Pluronic F127), Adcon-L (Gliatech), based on polylactic acid, Intergel (Lifecore Biomedical), based on hyaluronic acid, AdbA (Amitie), using natural polymers as raw materials, Spraygel (Confluent Surgical), based on spray-type polyethylene oxide, etc., have been developed, of which some are commercially available. However, the gel-type adhesion inhibitors are readily degraded and absorbed by the body (in an aqueous solution) before wounds heal, and thus, they have a problem of exerting low adhesion-preventing effects. Due to this problem, previously used adhesion inhibitors are known to exhibit adhesion-preventing effects of only about 50˜70% (J. M. Becker, et al., presented at Clinical Congress of Am. College of Surgeon, New Orleans, Oct. 22, 1995).
U.S. Pat. No. 4,141,973 by Balazs, et al. discloses the use of hyaluronic acid as a main component for inhibiting adhesion. However, as the hyaluronic acid is readily degraded in a living body, it dissolves relatively well, and its half-life in a living body is relatively short, that is, 1 to 3 days, so it cannot be retained in the body for the time necessary to inhibit adhesion, and is severely limited in functioning as an adhesion inhibitor.
U.S. Pat. No. 1,593,394 (product name: Intergel®) discloses a method of improving in vivo stability of a hyaluronic acid polymer by using trivalent ferric chloride (FeCl3), but the FDA has cancelled its registration due to inflammation and adverse effects caused by ferric chloride practically applied as a crosslinking agent in clinical trials.
In U.S. Pat. No. 5,939,485, Bromberg, et al. described a polymer network that had been developed, which is responsive to environmental stimuli, such as pH, temperature, and ionic strength. They used vinyl polymers, acryl polymers, and urethanes, which are non-degradable polymers, in a living body as the structural components of the polymer network, and used polyoxyalkylene polymers and cellulose polymers as the stimuli-sensitive polymers. However, if the non-degradable polymers as described above are used as structural components, they may generate a foreign body reaction because they are not degradable in a living body and have low biocompatibility.
As described above, non-degradable polymers cause inflammation in surrounding tissues, thus requiring reoperation for removal after a certain period of time, and biodegradable polymers have rather low adhesion-preventing effects, as compared with non-degradable polymers. Further, gel-type adhesion inhibitors are readily degraded and absorbed by the body before the wound heal, and thus, they exert low adhesion-preventing effects. Accordingly, there is a demand for a temperature-sensitive adhesion inhibitor to solve the disadvantages of non-degradable polymers and biodegradable polymers.
Poloxamer, a polymer manufactured by BASF, is known as a thermosensitive substance that exists in a solution state at a low temperature but gelates as temperature increases (see U.S. Pat. No. 4,188,373, U.S. Pat. No. 4,478,822 and U.S. Pat. No. 4,474,751). U.S. Pat. No. 5,939,485 by Bromberg, et al. describes that these poloxamers are substances capable of reversible gelation according to stimuli of pH, temperature, and ionic strength. Further, Steinleitner, et al. published an evaluation of the anti-adhesion efficacy of fluid gels having poloxamers as a basic composition [Fertility and sterility 57(2): 305 (1992)].
Generally known poloxamers have a structure of polyethylene oxide (PEO)-polypropylene oxide (PPO)-polyethylene oxide (PEO). For example, Poloxamer 407 has a gelation temperature of about 25° C. and its gelation is influenced by factors such as poloxamer grade, concentration, pH, additives, etc. In addition, the melting temperature of Poloxamer 407 is 56° C. and its specific gravity is 1.05. However, this poloxamer has physical properties such that it forms a polymer gel in aqueous solutions, but is easily dissolved in water. Therefore, poloxamer has a drawback in that it does not retain its gel state in a certain area for a time sufficient to inhibit adhesion.
Korean Patent Nos. 0416104B1 and 0565881B1 describe a method of improving in vivo stability of carboxymethyl cellulose used as a main component and poloxamer by ionic crosslinking of water-soluble alginate with divalent cations (Ca2+, Br2+, etc.). However, when this method is used, in vivo stability is slightly improved, but, in practice, tissue adhesiveness is reduced at the site of application and the applied solutions flow down from the tissues. Because of this problem, there are restrictions on the use of poloxamers in the peritoneal cavity/pelvic cavity/uterine cavity, which are the most common surgical sites among all surgical sites (about 50% or more), and poloxamers also have low adhesion-preventing effects.
Due to these problems, a variety of film-, fabric-, or gel-type adhesion inhibitors have been developed or commercialized, and until now have been clinically used, but products showing successful adhesion-preventing effects at all surgical sites have not yet been developed. Accordingly, there is a demand for the development of an ideal adhesion inhibitor which has superior biocompatibility, tissue adhesiveness, bioabsorbability, in-body stability, etc., and may be readily applied to all surgical sites.